Pharmacokinetic interactions between clozapine and valproic acid in patients with treatment-resistant schizophrenia: Does UGT polymorphism affect these drug interactions?

The combination of valproic acid (VPA) and clozapine (CLZ) is regularly prescribed for augmentation therapy in treatment resistant schizophrenia. The VPA has been shown to reduce norclozapine (NCLZ) plasma levels, but the mechanism of this interaction remains unknown. The aim of this study is to examine the differences between patients treated with CLZ and patients treated with CLZ plus VPA. For it, various factors have been evaluated. The study was based on plasma samples from CLZ and CLZ plus VPA treated patients (n = 61) subjected to routine therapeutic drug monitoring considering clinical data, smoking status, daily dose of CLZ and VPA, concomitant medications, albumin, and renal and hepatic function. Genotyping of polymorphisms of CYP1A2, CYP3A4/5, CYP2C19, ABCB1, UGT2B10 and CYP2C19 were performed by real time PCR. CYP2D6 were genotyped using competitive allele-specific PCR and by a long PCR based method. Plasma CLZ and NCLZ concentrations were measured by Liquid Chromatography-Tandem masses (LC-MS/MS) and plasma VPA by Ultraviolet-Visible (UV-vis) spectrophotometric immunoassay. The patients presented adequate CLZ levels in relation to the dose. However, NCLZ levels were excessively low and the CLZ/NCLZ ratio very high. Patients with UGT2B10 GT (rs61750900) genotype showed lower NCLZ plasma levels and C/D NCLZ, and higher CLZ/NCLZ ratio versus patients with UGT2B10 GG genotype. VPA, smoking, the presence of UGT2B10 GT genotype and having low albumin levels indicate that the CLZ/NCLZ ratio is affected, mostly coinciding with decreased NCLZ levels and possibly with an increased risk of neutropenia.

Exploring the usefulness of plasma level determination and pharmacogenetics for patients treated with clozapine.

Aims: The aims of the present study were to assess the variance of plasma clozapine (CLZ) levels and to identify the influence of sociodemographic and pharmacogenetic factors on it and to introduce these tools in a clinical setting. Patients & methods: CLZ concentration was measured and genetic variants of CLZ pharmacokinetic and pharmacodynamic factors were assessed in 23 patients with psychotic disorders. Results: A significant association between mean concentration/dose ratio (C/D) and smoking status, age and weight were found. There was a significant difference in mean plasma CLZ levels and gender. The rs762551 AA genotype in smokers had a significantly lower C/D. Conclusion: In addition to classical factors, monitoring of plasma concentrations together with pharmacogenetics led to greater individualization of treatment.

Patients receiving clozapine (CLZ) usually show a variability in plasma concentrations. This study assesses the variance of plasma CLZ levels and explores the influence of gender, smoking, age, weight and genetics. Plasma CLZ levels were measured in 23 patients with psychotic disorders. Additionally, genetic analysis of genes involved in CLZ metabolism were carried out. An association between plasma concentration of CLZ adjusted for daily dose and smoking status, weight and age were found. Plasma CLZ and gender were also associated. A mutation of a genetic variant related to CLZ metabolism showed in smokers lower CLZ concentration adjusted for daily dose, explaining poor treatment response. Individual dose modification in these patients improved the clinical situation.

Implementation of pharmacogenetics in a clozapine treatment resistant patient: a case report.

We report the case of a young Caucasian male with disorganized chronic schizophrenia, an active smoker and nonresponder to 400 mg of clozapine/day. Therapeutic clozapine monitoring was analyzed revealing a low clozapine:norclozapine ratio. An additional pharmacogenetic test was carried out showing that the patient carried *1F variant (CYP1A2 gene), which has been associated with nonresponse to clozapine in smoker patients. A genetic variation in the SLC6A4 gene was also found, which could be related to the poor response to clozapine. The remainder of the genes analyzed (CYP2D6, ABCB1 and HTR2A) were not directly associated with the patient's phenotype. The dose of clozapine was increased to 600 mg/day, reaching the therapeutic range. This case shows how pharmacogenetics can help in understanding the value of plasma levels to provide clinical improvement.

The linguistic signature of hallucinated voice talk in schizophrenia.

Very few studies have investigated the formal linguistic aspects of auditory verbal hallucinations (AVHs), though speech is a defining aspect of AVHs. Hallucinated speech heard by 19 patients with schizophrenia and highly frequent voices was obtained online, as and when they spoke, and annotated for pre-selected linguistic variables. Results showed that, consistently across the sample, (i) the grammatical first Person was significantly less represented than both second and third person, and often absent altogether; (ii) overwhelmingly, isolated clauses with no grammatical connectivity (parataxis) were produced, as compared with subordinations, coordinations, and adjunctions; (iii) in all participants except one, virtually no noun phrases (NPs) were anaphoric ones, back-referring to previous NPs, illustrating again a lack of connectivity across utterances. (vi) Sentence-level content was largely personal rather than impersonal, and in impersonal utterances, it was generally vague. (v) Formal syntactic errors were consistently nearly absent, as were semantic level errors such as paraphasias. Voice talk was not generally stereotyped. These results indicate that, despite a certain amount of individual variation, there is a distinctive linguistic profile to voice speech, which constrains theories of AVHs and their neurocognitive basis.